Background Recurrent head and neck squamous cell carcinoma (HNSCC) remains a difficult cancer to treat. Here, we describe a patient with HNSCC who had complete response to methotrexate (MTX) after progressing on multiple cytotoxic agents, cetuximab, and AMG-479 (monoclonal antibody against insulin-like growth factor-1 receptor [IGF-1R]). Methods The clinical information was collected by a retrospective medical record review under an Institutional Review Board–approved protocol. From 4 tumors and 2 normal mucosal epithelia, global gene expression, and IGF-1R and dihydrofolate reductase (DHFR) protein levels were determined. Results Effective target inhibition in the tumor was confirmed by the decreased protein levels of total and phospho-IGF-1R after treatment with AMG-479. Decreased level of DHFR and conversion of a gene expression profile associated with cetuximab-resistance to cetuximab-sensitivity were also observed. Conclusion This suggests that the combination of AMG- 479 and MTX or cetuximab may be a promising therapeutic approach in refractory HNSCC.

The recommended phase II dose of tecogalan sodium on this schedule is 390 mg/m2 over 24 hours. Other schedules including continuous administration should be investigated to maximize the efficacy of this novel angiogenesis inhibitor.

3031 Background: In an effort to enhance the efficacy of vascular endothelial growth factor (VEGF) pathway blockade in mRCC we initiated a Phase I-II trial of combination S and B to block VEGFR signaling and VEGF binding, as well as, platelet derived growth factor receptor β (PDGFR) signaling. Methods: Pts with measurable (RECIST) mRCC, adequate organ function, and PS 0–1 were eligible for this trial. Cohorts of 6 pts were enrolled at 3 sites to define the MTD and DLT of the combination of S and B. The schedule was B IV q 14 days and S daily with cycles of 28 days. Response and toxicity were assessed at the end of 2 cycles. Dose levels began with S at 200mg BID and B at 5 mg/kg (level 1) with the hope to reach phase II doses of both agents (S at 400mg BID and B at 10mg/kg). The MTD or the phase II dose of each agent would then be administered to up to 45 pts with mRCC, clear cell histology, and prior nephrectomy. Results: A total of 18 patients have been enrolled to date, with 15 completing their first response evaluation. Pts were median age 61 years (46–74 range); M/F: 15/3; PS: 0/1= 12/6; 17 clear cell, 1 chromophobe, 11 prior nephrectomy; 4 with prior cytokine therapy. Two pts in level 1 experienced DLT with recurrent and intolerable (grade 3) hand-foot syndrome (HFS). An additional 6 patients were treated at dose level -1 (S at 200mmg QD and B at 3mg/kg) with no DLTs. Six more pts have been treated at dose level 1 with Vit B6 at 300mg/d in an attempt to minimize HFS. Toxicity data in this cohort is incomplete. Additional toxicities among the 18 pts included grade 3 hypertension (4), grade 3 proteinuria (2), and grade 2 stomatitis (3). Responses including 4 objective PRs, and 4 pts with 20–30% regression have been seen in the 14 evaluated pts. Only 2 patients have had disease progression. Conclusions: The phase II doses for this combination have not yet been established, but will likely be lower than the full phase II doses of the individual agents. The toxicities from HFS (primarily) and hypertension and stomatitis appear to be limiting. Even at the initial low doses of S and B, significant anti-tumor activity has been observed. The completion of this phase I trial will be reported. The phase II studies in mRCC are highly anticipated. Support by phase I contract UO-1 CA099177 [Table: see text]